US commercial health plan coverage dynamics in pulmonary arterial hypertension therapies.

BACKGROUND: Health plan coverage is central to patient access to care, especially for rare, chronic diseases. For specialty drugs, coverage varies, resulting in barriers to access. Pulmonary arterial hypertension (PAH) is a rare, progressive, and fatal disease. Guidelines suggest starting or rapidly escalating to combination therapy with drugs of differing classes (phosphodiesterase 5 inhibitors [PDE5is], soluble guanylate cyclase stimulators [sGC stimulators], endothelin receptor antagonists [ERAs], and prostacyclin pathway agents [PPAs]). OBJECTIVE: To assess the variation in commercial health plan coverage for PAH treatments and how coverage has evolved. To examine the frequency of coverage updates and evidence cited in plan policies. METHODS: We used the Tufts Medical Center Specialty Drug Evidence and Coverage database, which includes publicly available specialty drug coverage policies. Overall, and at the drug and treatment class level, we identified plan-imposed coverage restrictions beyond the drug's US Food and Drug Administration label, including step therapy protocols, clinical restrictions (eg, disease severity), and prescriber specialty requirements. We analyzed variation in coverage restrictiveness and how coverage has changed over time. We determined how often plans update their policies. Finally, we categorized the cited evidence into 6 different types. RESULTS: Results reflected plan coverage policies for 13 PAH drugs active between August 2017 and August 2022 and issued by 17 large US commercial health plans, representing 70% of covered lives. Coverage restrictions varied mainly by step therapy protocols and prescriber restrictions. Seven plans had step therapy protocols for most drugs, 9 for at least one drug, and 1 had none. Ten plans required specialist (cardiologist or pulmonologist) prescribing for at least one drug, and 7 did not. Coverage restrictions increased over time: the proportion of policies with at least 1 restriction increased from 38% to 73%, and the proportion with step therapy protocols increased from 29% to 46%, with generics as the most common step. The proportion of policies with step therapy protocols increased for every therapy class with generic availability: 18% to 59% for ERAs, 33% to 77% for PDE5is, and 33% to 43% for PPAs. The proportion of policies with prescriber requirements increased from 24% to 48%. Plans updated their policies 58% of the time annually and most often cited the 2019 CHEST clinical guidelines, followed by randomized controlled trials. CONCLUSIONS: Plan use of coverage restrictions for PAH therapies increased over time and varied across both drugs and plans. Inconsistency among health plans may complicate patient access and reduce the proportion who can persist on PAH treatments.

Hospitalization-related costs associated with oral agents targeting the prostacyclin pathway for pulmonary arterial hypertension.

AIMS: Pulmonary arterial hypertension (PAH) is a rare, progressive, and ultimately fatal form of the broader condition pulmonary hypertension. ESC/ERS guidelines recommend therapy targeting the prostacyclin pathway for patients not achieving low-risk mortality status. Currently, only oral selexipag (OS) and oral treprostinil (OT) have this mechanism of action and are available in the United States (US). A recent database analysis has shown significantly lower hospitalization risk for patients treated with OS versus OT. Nevertheless, differences in hospitalization and treatment costs among PAH patients taking oral prostacyclin pathway agents (PPAs) in the US healthcare system remain unclear. This study aims to estimate the difference in costs for patients who achieve a stable maintenance dose from a US payer perspective. MATERIALS AND METHODS: We developed a cost calculator including direct medical costs from the US third-party payer perspective to estimate PAH-related hospitalizations and costs associated with oral PPA use over 2 years, in a hypothetical US payer plan with 1 million members. The treatment-eligible population was estimated from real-world epidemiological data. Treatment-specific hospitalizations were estimated from a study using the Optum Clinformatics administrative claims database. Influence of each model parameter was tested in one-way sensitivity analyses (OWSA), while scenario analysis tested the impact of key assumptions. RESULTS: For 78 PAH patients included in the model, the base case scenario estimated total costs of $46,736,768 with 98 PAH-related admissions for OS, and total costs of $60,113,620 and 161 PAH-related admissions over 2 years for OT. Using OS was associated with 22.3% cost reduction and 39.1% hospitalizations averted; the number of patients needed treated with selexipag to avoid one hospital admission was 1.23. OWSA indicated medication cost was the most sensitive parameter, followed by population parameters. LIMITATIONS AND CONCLUSIONS: OS use over 2 years would result in lower total, drug, and hospitalization-related costs compared with OT, thus providing financial savings for payers.

Impact of selexipag use within 12 months of pulmonary arterial hypertension diagnosis on hospitalizations and medical costs: A retrospective cohort study.

BACKGROUND: Oral selexipag, a prostacyclin pathway agent (PPA), is effective in patients with pulmonary arterial hypertension (PAH). The objective of this study is to assess the impact of initiating oral selexipag within 12 months of diagnosis on health outcomes. METHODS: This retrospective cohort study used data from Optum's de-identified Clinformatics® Data Mart Database. PAH patients between 1 October 2015 and 30 September 2019 were included. Patients were also required to have received PAH medication within 12 months of their initial diagnosis. Study groups included patients who initiated selexipag within 12 months of PAH diagnosis (SEL ≤ 12) and those who did not initiate any PPA within 12 months of PAH diagnosis (No PPA ≤ 12). Inverse probability of treatment weighting was used to remove potential confounding between groups. Cox and Poisson regression models were used to compare hospitalization and disease progression. Generalized linear model with gamma distribution and log link was used to compare costs. RESULTS: SEL ≤ 12 had lower rate of all-cause hospitalizations (rate ratio: 0.76, 95% confidence interval [CI]: 0.60, 0.96) versus no PPA ≤ 12, but no differences in PAH-related hospitalization rate (rate ratio: 1.03, 95% CI: 0.79, 1.33) or risk of disease progression (hazard ratio: 1.01, 95% CI: 0.71, 1.44). SEL ≤ 12 incurred lower all-cause (mean difference: -$23 623; 95% CI: -35 537, -8512) and PAH-related total medical costs (mean difference: -$12 927; 95% CI: -19 559, -5679) versus no PPA ≤ 12. CONCLUSION: Selexipag initiation within 12 months of PAH diagnosis demonstrated reductions in all-cause hospitalization rate and medical costs.

Assessment of Knowledge, Attitude, and Practice Patterns in Pulmonary Arterial Hypertension among Cardiologists and Pulmonologists: Evidence from Turkey.

Background and Objectives: Pulmonary arterial hypertension (PAH) is a rare chronic disease of the small pulmonary arteries that causes right heart failure and death. Accurate management of PAH is necessary to decrease morbidity and mortality. Understanding current practices and perspectives on PAH is important. For this purpose, we intended to determine physicians' knowledge, attitudes, and practice patterns in adult pulmonary arterial hypertension (PAH) in Turkey. Materials and Methods: Between January and February 2022, an online questionnaire was sent via e-mail to all cardiologists and pulmonologists who were members of the Turkish Society of Cardiology (TSC) and the Turkish Thoracic Society (TTS). Results: A total of 200 physicians (122 pulmonologists and 78 cardiologists) responded to the questionnaire. Cardiologists were more frequently involved in the primary diagnosis and treatment of PAH than pulmonologists (37.2% vs. 23.8%, p = 0.042). More than half of the physicians had access to right heart catheterization. In mild/moderate PAH patients with a negative vasoreactivity test, the monotherapy option was most preferred (82.8%) and endothelin receptor antagonists (ERAs) were the most preferred group in these patients (73%). ERAs plus phosphodiesterase-5 inhibitors (PDE-5 INH) were the most preferred (69%) combination therapy, and prostacyclin analogues plus PDE-5 INH was preferred by only pulmonologists. Conclusions: Overall, clinical management of patients with PAH complied with guideline recommendations. Effective clinical management of PAH in specialized centers that having right heart catheterization achieve better outcomes.

Echocardiographic Assessment of Pulmonary Arterial Hypertension Following Inhaled Nitric Oxide in Infants with Severe Bronchopulmonary Dysplasia.

OBJECTIVES: Inhaled nitric oxide (iNO) is an effective pulmonary vasodilator. However, the efficacy of iNO in former premature infants with established bronchopulmonary dysplasia (BPD) has not been studied. This study aimed to determine the efficacy of iNO in reducing pulmonary artery pressure in infants with severe BPD as measured by echocardiography. STUDY DESIGN: Prospective, observational study enrolling infants born at less than 32 weeks gestation and in whom (1) iNO therapy was initiated after admission to our institution, or (2) at the outside institution less than 48 h before transfer and received an echocardiogram prior to iNO initiation, and (3) had severe BPD. Data were collected at three time-points: (1) before iNO; (2) 12-48 h after initiation of iNO; and (3) 48-168 h after initiation of iNO. The primary outcome was the effect of iNO on pulmonary artery pressure measured by echocardiography in patients with severe BPD between 48 and 168 h after initiating iNO therapy. RESULTS: Of 37 enrolled, 81% had echocardiographic evidence of pulmonary arterial hypertension (PAH) before iNO and 56% after 48 h of iNO (p = 0.04). FiO2 requirements were significantly different between time-points (1) and (3) (p = 0.05). There were no significant differences between Tricuspid Annular Plane Systolic Excursion (TAPSE) Z-Scores, time to peak velocity: right ventricular ejection time (TPV:RVET), and ventilator changes. CONCLUSIONS: Although we found a statistically significant reduction of PAH between time-point (1) and (3), future trials are needed to further guide clinical care.

Cost-utility of ambrisentan and bosentan for pediatric pulmonary arterial hypertension.

INTRODUCTION: Despite the increasing evidence supporting the efficacy of ambrisentan and bosentan in improving functional classes among pediatric patients with pulmonary arterial hypertension (PAH), there is a lack of information regarding their cost implications. Therefore, the objective of this study is to assess the cost-utility of bosentan compared to ambrisentan for the treatment of pediatric patients with PAH in Colombia. METHODS: We employed a Markov model to estimate the costs and quality-adjusted life-years (QALYs) associated with the use of ambrisentan or bosentan in pediatric patients diagnosed with pulmonary arterial hypertension (PAH). To ensure the reliability of our findings, we conducted sensitivity analyses to assess the robustness of the model. In our cost-effectiveness analysis, we evaluated the outcomes at a willingness-to-pay (WTP) threshold of US$5,180. RESULTS: The expected annual cost per patient receiving ambrisentan was estimated to be $16,055 (95% CI 15,937 -16,172), while for bosentan it was $14,503 (95% CI 14,489 -14,615). The QALYs per person estimated for ambrisentan were 0.39 (95% CI 0.381-0.382), whereas for bosentan it was 0.40 (95% CI 0.401-0.403). CONCLUSION: Our economic evaluation shows that ambrisentan is not cost-effective regarding bosentan to in treating pulmonary arterial hypertension in C.

Eficacia y seguridad de treprostinil o selexipag adicionado a sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional OMS III, con fracaso a sildenafilo más bosentán / Efficacy and safety of treprostinil or selexipag added to sildenafil plus bosentan, in adult patients with pulmonary arterial hypertension, WHO functional class III, with failure to sildenafil plus bosentan

ANTECEDENTES> En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el que expone la evaluación de la eficacia y seguridad de treprostinil o selexipag en adición a sildenafil más bosentán, comparado con el esquema sildenafil más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional de la Organización Mundial de la Salud (OMS) III, con fracaso a la administración conjunta de sildenafil más bosentán. Así, Oscar Nelson Aguirre Zurita, médico cardiólogo del Servicio de Cardiología del Instituto Nacional Cardiovascular - INCOR envió al IETSI la solicitud de autorización de uso del producto farmacéutico treprostinil no incluido en el Petitorio Farmacológico de EsSalud siguiendo la Directiva N° 003-IETSI-ESSALUD-2016. ASPECTOS GENERALES: Los aspectos generales de la hipertensión arterial pulmonar (HAP) se han descrito previamente en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N.° 012- DETS-IETSI-2021 (IETSI-EsSalud 2021). Brevemente, la HAP es una enfermedad compleja y progresiva caracterizada por un aumento de la presión en la arteria pulmonar. Los pacientes comúnmente experimentan dificultad para respirar, hinchazón de tobillos y piernas, mareos o desmayos. En promedio, los pacientes viven entre cinco y siete años después del diagnóstico. La enfermedad afecta más comúnmente a personas entre 20 y 40 años de edad, y es más común en mujeres que en hombres. La Organización Mundial de la Salud (OMS) ha desarrollado un sistema de clasificación de HAP basado en el nivel de función y los síntomas. Los pacientes pueden tener Clase Funcional (CF) I a IV, con números crecientes que reflejan una mayor gravedad (CADTH 2015a). La HAP es rara, con una incidencia estimada de hasta 7.6 casos por millón de adultos y una prevalencia de hasta 26-100 por millón de adultos. La morbilidad y la mortalidad siguen siendo significativas y el diagnóstico y tratamiento tempranos son esenciales (Hirani et al. 2020). METODOLOGÍA: Se realizó una búsqueda sistemática utilizando las bases de datos PubMed, Cochrane Library, y LILACS. Además, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorporagáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros. Asimismo, se revisó la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en hipertensión pulmonar, tales como: American College of Chest Physicians (CHEST), European Society of Cardiology (ESC) y la European Respiratory Society (ERS). Se realizaron búsquedas manuales complementarias en las listas de referencias de los textos completos evaluados. RESULTADOS: La búsqueda de literatura permitió identificar siete publicaciones: dos GPC realizadas por CHEST (Klinger et al. 2019) y ESC-ERS (Humbert et al. 2022); dos ETS elaboradas por HAS (HAS 2011) y CADTH (CADTH 2006); dos ECA (Simonneau et al. 2002; McLaughlin et al. 2003); y un estudio observacional (Barst et al. 2006). CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso de treprostinil o selexipag adicionado a sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional OMS III, con fracaso a sildenafilo más bosentán.

Phosphodiesterase 5 Inhibitor for Pediatric Pulmonary Arterial Hypertension: A Cost-Utility Analysis.

OBJECTIVES: Despite the growing evidence of efficacy, scarce information exists regarding the cost of tadalafil to improve the functional classes of pediatric patients with pulmonary arterial hypertension. This study aims to determine the cost-utility of tadalafil compared sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. METHODS: A Markov model was developed to compare expected costs, outcomes, and quality-adjusted life-years of sildenafil and tadalafil in pediatric patients with pulmonary arterial hypertension. The model was analyzed probabilistically, and a value of information analysis was conducted to inform the value of conducting further research to reduce current uncertainties in the evidence base. Cost-effectiveness was evaluated at a willingness-to-pay value of US $5180. RESULTS: The mean incremental cost of tadalafil versus sildenafil is US $15 270. The 95% credible interval for the incremental cost ranges from US $28 033.65 to US $5940.86. The mean incremental benefit of tadalafil versus sildenafil is 1.00 quality-adjusted life-years (QALY). The 95% credible interval for the incremental benefit ranges from 1.88 to 0.31 QALY. The expected incremental cost per QALY is estimated at US $15 286. There is a probability less than 1% that tadalafil is more cost-effective than sildenafil at a threshold of US $5180 per QALY. Form the value of information analysis, the theoretical upper bound on the value of further research was US $9.298 for Colombia. CONCLUSION: Our economic evaluation shows that tadalafil is not cost-effective regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines.

Comparative evaluation of costs and healthcare resource utilization of oral selexipag versus inhaled treprostinil or oral treprostinil in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH), a rare vasculopathy progressively leading to right heart failure and death, is associated with considerable economic burden. Oral prostacyclin pathway agents (PPAs) like selexipag and treprostinil address an underlying PAH pathway, yet are often under-utilized. Data on head-to-head cost comparison of various PPAs is lacking. METHODS: In this retrospective study using a large health claims database, we compared the per-patient-per-year (PPPY) costs and healthcare resource utilization (HRU) among PAH patients taking either oral selexipag, inhaled treprostinil or oral treprostinil in the United States between July 2015 and March 2020. Patients with ≥1 prescription for one of the drugs of interest, ≥1 in-patient pulmonary hypertension (PH) diagnosis, or ≥ 2 outpatient PH diagnoses were included in this study. Baseline differences between the three groups were adjusted using an inverse probability of treatment weighting approach. 411 patients were selected for the final study cohorts. RESULTS: All-cause hospitalization costs were highest for oral treprostinil ($39,983) compared to oral selexipag ($20,635) and inhaled treprostinil ($16,548; p = .037). Total PAH-related medical costs were 40% lower for patients on oral selexipag compared to patients on oral and inhaled treprostinil ($24,351 vs. $40,398 and $40,339, respectively; p = .006). PAH-related outpatient visits were lowest for patients on oral selexipag (14 PPPY visits) compared to oral treprostinil (16 PPPY visits) and inhaled treprostinil (22 PPPY visits; p = .001). CONCLUSIONS: Compared to oral and inhaled treprostinil, oral selexipag may incur lower medical costs and reduce PAH related outpatient visits for patients with PAH.

Ambrisentan for in pediatric pulmonary arterial hypertension: A cost-utility analysis.

INTRODUCTION: Despite the growing evidence of efficacy, little is known regarding the efficiency of ambrisentan to decrease cost and improve the functional classes of pediatric patients with pulmonary arterial hypertension. This study aims to determine the cost-utility of ambrisentan regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. METHODS: A decision tree model was used to estimate the cost and quality-adjusted life-years (QALYs) of ambrisentan, or sildenafil in pediatric patients with pulmonary arterial hypertension. Multiple sensitivity analyses were conducted to evaluate the robustness of the model. Cost-effectiveness was evaluated at a willingness-to-pay (WTP) value of US$5180. RESULTS: The base-case analysis showed that compared with sildenafil, ambrisentan was associated with higher costs and higher QALYs. The expected annual cost per patient with ambrisentan was US$16,105 and with sildenafil was US$1431. The QALYs per person estimated with ambrisentan was 0.40 and for sildenafil was 0.39. The estimated improvement in quality of life and reduced costs results in an estimate of economic dominance for sildenafil over ambrisentan. CONCLUSION: Our economic evaluation shows that ambrisentan is not cost-effective regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines.

Inhaled treprostinil vs iloprost: Comparison of adherence, persistence, and health care resource utilization in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is associated with a substantial clinical and economic burden. Inhaled prostacyclins are a well-established part of pharmacotherapy for PAH. There are differences between inhaled therapies in the burden imposed by administration frequency. Simpler and less time-consuming inhaled PAH therapies may improve both adherence and persistence and potentially affect outcomes. OBJECTIVE: To compare real-world health care resource use, costs, and treatment adherence and persistence in patients with PAH who initiated inhaled treprostinil or iloprost. METHODS: Adult patients with 1 inpatient or 2 outpatient medical claims separated by at least 30 days with a diagnosis of PAH were identified using International Classification of Diseases, Ninth Revision or Tenth Revision, Clinical Modification codes with a pharmacy claim for inhaled treprostinil or iloprost. Patients were required to be continuously enrolled in the health plan for 6 months prior to and 12 months after the index date. A proportion of days covered of 0.8 or more was considered adherent; persistence was no gap in therapy for at least 60 days. All-cause health care resource utilization and all-cause costs were assessed. RESULTS: 405 and 62 patients were included in the inhaled treprostinil and iloprost cohorts, respectively. Adherence (50.9% and 22.6%; P < 0.0001) and persistence (6 months, 65.2% vs 35.5%; 12 months, 46.7% vs 16.1%; log-rank P < 0.001) were significantly better with inhaled treprostinil. Post-index allcause inpatient admissions (39.3% vs 54.8%; P = 0.02) and post-index emergency department (ED) utilization (36.3% vs 50.0%; P = 0.04) were lower with inhaled treprostinil. Among patients who were persistent with therapy through 12 months, there was no significant difference between groups in mean (SD) all-cause total costs ($266,462 [137,324] vs $262,826 [112,452] for inhaled treprostinil vs iloprost, respectively; P = 0.98). CONCLUSIONS: The results suggest that inhaled treprostinil is less burdensome, is associated with greater adherence and persistence, and may reduce all-cause hospitalizations and ED visits. DISCLOSURES: This study was funded by the United Therapeutics Corporation to obtain data for this analysis and compose the manuscript. Dr Burger has served as clinical investigator in multicenter interventional trials sponsored by United Therapeutics but did not receive any direct compensation. Drs Wu and Morland and Mr Classi are employees of United Therapeutics Corporation and own stock/shares in the company.

Assessment of Inhaled Treprostinil Palmitil, Inhaled and Intravenous Treprostinil, and Oral Selexipag in a Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension.

Treprostinil palmitil (TP), a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE), has beneficial effects in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) that compare favorably to the oral phosphodiesterase 5 inhibitor (PDE5) sildenafil. In this study in male Sprague-Dawley rats, a dry powder formulation of TP (TPIP) was compared with inhaled and intravenous TRE and oral selexipag to evaluate inhibition of hemodynamic and pathologic changes in the lungs and heart induced by Su/Hx challenge. Su (20 mg/kg) was injected subcutaneously followed by 3 weeks of Hx (10% O2/balance N2) and then initiation of test article administration over 5 weeks with room air breathing. Hemodynamics and histopathology were measured at the end of the study. Su/Hx challenge approximately doubled the mean pulmonary arterial blood pressure (mPAP) and the Fulton index, decreased cardiac output (CO), doubled the wall thickness and muscularization of the small (10-50 µm) and medium (51-100 µm) sized pulmonary arteries, and increased the percentage of obliterated pulmonary blood vessels. Even though inhaled TRE (65 µg/kg, 4× daily), intravenous TRE (810 ng/kg/min), and oral selexipag (30 mg/kg, twice daily) provided some beneficial effects against the Su/Hx challenge, the overall benefit was generally greater with TPIP at high dose (117 µg/kg, once daily). These results demonstrate that TPIP compares favorably to inhaled and intravenous TRE and oral selexipag with respect to inhibition of the pathophysiological changes induced by Su/Hx challenge in rats. SIGNIFICANCE STATEMENT: Treprostinil palmitil (TP) is a long-acting pulmonary vasodilator prodrug of treprostinil (TRE) formulated for inhaled administration by dry powder [treprostinil palmitil inhalation powder (TPIP)]. Comparison of the activity of TPIP, inhaled and intravenous TRE, and oral selexipag in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension demonstrated that each of these drugs exert protection against the hemodynamic and histopathological changes induced by the Su/Hx challenge, with the greatest effect on these changes produced by TPIP.

Association Between Copayment and Adherence to Medications for Pulmonary Arterial Hypertension.

Background Pharmacologic treatment for pulmonary arterial hypertension (PAH) improves exercise capacity, functional class, and hemodynamic indexes. However, monthly prescription costs often exceed $4000. We examined associations between (1) medication copayment and (2) annual household income with adherence to pulmonary vasodilator therapy among individuals with PAH. Methods and Results We used administrative claims data from an insured population in the United States to identify individuals diagnosed with PAH between 2015 and 2020. All individuals had ≥1 medication claim for endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, prostanoids or prostacyclin receptor agonists, or the soluble guanylate cyclase stimulator riociguat. We defined copayments as low, medium, or high, as determined by their distributions for each medication class. Annual household income was categorized as <$40 000, $40 000 to $74 999, and ≥$75 000. The primary outcome was medication adherence, defined by proportion of days covered ≥80%. We studied 4025 adults (aged 65.9±13.3 years; 71.2% women). Compared with those with annual household income ≥$75 000, individuals in the <$40 000 and $40 000 to $74 999 categories had no significant differences in medication adherence. Compared with those with low copayments, individuals with high copayments had decreased adherence to prostanoids (odds ratio [OR], 0.36 [95% CI, 0.20-0.65]; P<0.001) and combination therapy with endothelin receptor antagonist and phosphodiesterase type-5 inhibitor (OR, 0.61 [95% CI, 0.38-0.97]; P=0.03). Conclusions We identified associations between copayment and adherence to prostanoids and combination therapy among individuals with PAH. Copayment may be a structural barrier to medication adherence and merits inclusion in studies examining access to pharmacotherapy among individuals with PAH.

Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients. METHODS: We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed. RESULTS: We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55-0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47-0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38-0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48-0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742-0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality (R2trial, 0.35 [95% CI, 0.10-0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical. CONCLUSIONS: PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42020178949.

Ambrisentana, bosentana, iloprosta, selexipague e sildenafila para o tratamento de pacientes com hipertensão arterial pulmonar / Ambrisentan, bosentan, iloprost, selexipag and sildenafil for the treatment of patients with pulmonary arterial hypertension

INTRODUÇÃO: A Hipertensão Arterial Pulmonar (HAP) é uma doença grave e progressiva que resulta em disfunção ventricular direita e comprometimento na tolerância à atividade física, podendo levar à insuficiência cardíaca direita, incapacidade e morte prematura. Possui incidência estimada de 1,9 a 3,7 novos casos/milhão de habitantes ao ano. Atualmente, são disponíveis cinco medicamentos aprovados pela Anvisa e incorporados no Sistema Único de Saúde (SUS), que incluem antagonistas do receptor de endotelina (ERA) (ambrisentana e bosentana); inibidores da fosfodiesterase 5 (PDE5i) (sildenafila) e atuantes na via da prostaciclina (PGI2), que são os análogos da PGI2 (iloprosta). O atual Protocolo Clínico e Diretrizes Terapêuticas da Hipertensão Arterial Pulmonar informa que a avaliação da Conitec foi contrária à utilização destes fármacos em terapia combinada, por falta de estudos comprobatórios de eficácia e pelos riscos de eventos adversos potencialmente graves ainda não avaliados adequadamente. A indicação de incorporação é a terapia combinada destes medicamentos e sildenafila em alta dose, como alternativas complementares de tratamento. Assim o objetivo deste relatório foi analisar as evidências científicas disponíveis sobre eficácia, efetividade, segurança, custoefetividade e impacto orçamentário do ambris